The long-term project objective is the commercialization of a safe, effective, easy to use, and painless polynucleotide vaccine delivery system that can be used in polynucleotide vaccines for biodefense against NIAID Category A, B and C Pathogens. Polynucleotide vaccines are on the forefront of vaccine development. They are important because of the fast development times possible and because cell mediated immune responses can be induced. The delivery system proposed here will be effective for most polynucleotide vaccines. This delivery system specifically addresses the requirement as presented in the NIAID Strategic Plan for Biodefense Research, February 2002, page 8. In addition to Biodefense, this system will provide effective polynucleotide vaccine delivery for less lethal viruses, some cancers and some third world diseases. The defense and commercial applications are extensive. The polynucleotide vaccine delivery system described here uses a microneedle array with the polynucleotide coated right on the needle in the array. There are hundreds of needles each about 0.15 mm long. This array in inserted into the skin with the needle penetrating to about the basal lamina. After insertion the polynucleotide leaves the needle surface and an electric field is used to permeabilize dendritic and epithelial cell membranes to permit the polynucleotide to enter the cell. The system will be tested with the WRAIR/Cyto Pulse dengue DNA vaccine which will be used as a model for hemorrhagic fever viruses and the USAMRIID vaccinia DNA plasmid which is the primary vaccine for small pox. The specific aims of this project are to design and develop to FDA QSR Standards the vaccine delivery system prototype and to test the prototype in a human trial. This is a fast-track application. In Phase I, a system design will be completed including the hand-piece, microneedle array and miniature waveform generator. The coating chemistry and specific waveforms will be optimized in mice. In Phase II, a prototype of the final design will be completed. Safety and efficacy will be demonstrated in mice and safety will be demonstrated in humans.